CD1d is an MHC class I-like protein and the antigen presenting molecule recognized by a conserved population of CD4+ or CD4-CD8- (double negative), NKR-P1 plus T cells that use an invariant TCRalpha chain and produce large amounts of IL-4 and IFNgamma (invariant NKR-P1 T cells). Recent studies in humans and mice have indicated a role for invariant NKR-P1 T cells in augmenting Th1 immune responses. The loss of invariant NKR-P1 T cells and defects in IL-4 production by these cells have been reported in several autoimmune diseases, including human type 1 diabetes. Invariant NKR-P1 T cells can also mediate anti-tumor effects of IL-12 and loss of these cells in Cd1d knockout mice can increase susceptibility to viral infection. These observations indicate that a physiological function for CD1d reactive invariant NKR-P1 T cells is to augment cell mediated Th1 immunity in response to appropriate immunological stimuli, with the autoimmune pathology linked to these cells reflecting this same Th1 inducing activity. The objectives of this proposal are to test this hypothesis and determine the mechanisms through which invariant NKR-P1 T cells modulate immune responses. Aim 1 will assess invariant NKR-P1 T cell function in humans prospectively in a series of normal donors versus autoimmune patients and patients enrolled in an IL- 12 clinical trial. Aim 2 will assess human CD1d+ T cells, B cells, and/or monocytes as target cells for invariant NKR-P1 T cells and for a novel population of bone marrow derived CD1d reactive T cells we have recently isolated. Aim 3 will assess changes in murine invariant NKR-P1 T cells in a viral infection model and, in CD1d knockout mice, will directly assess the contribution of CD1d and invariant NKR-P1 T cells to cytolytic T cell responses. The long term goals are to exploit CD1d reactive T cell populations as markers of immunological status and as therapeutic targets for drugs to boost Th1 responses (in the case of pathogens or vaccines) or suppress Th1 responses (in the setting of autoimmune disease).